CN103214426A - Production method of aprepitant morpholine key intermediate body or aprepitant morpholine salt - Google Patents
Production method of aprepitant morpholine key intermediate body or aprepitant morpholine salt Download PDFInfo
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Abstract
The invention provides a production method of (2R, 3R)-2-[(1R/S)-1-[3, 5-bis(trifluoromethyl) phenyl]ethyoxyl]-3-(4-fluorophenyl) morpholine or a salt thereof. The production method comprises the following steps of (1) carrying out condensation on a morpholine-2-alcohol derivative shown in the formula (1) and a compound shown in the formula (11) to obtain a compound shown in the formula (12); and (2) removing a protection group on a nitrogen atom of the compound shown in the formula (12), and collecting (2R, 3R)-2-[(1R/S)-1-[3,5-bis(trifluoromethyl) phenyl]ethyoxyl]-3-(4-fluorophenyl) morpholine or the salt thereof from a reaction system. The routine is simple to operate, the condition is moderate, the after-treatment is convenient, the process route is stable, the reagent is cheap and easy to obtain, and a good positive progress effect and a real application value can be realized. In addition, the production method has the advantages that the production method is suitable the industrialized production. The reaction general formula is shown in the specification.
Description
Technical field
The present invention relates to A Rui smooth intermediate (2R, 3R)-2[(1R/S)-1-[3, two (trifluoromethyl) phenyl of 5-] oxyethyl group]-preparation method of 3-(4-fluorophenyl) morpholine or its salt.
Background technology
A Rui smooth (Aprepitant) is a kind of NK1 receptor antagonist by Merck ﹠ Co., Inc.'s exploitation listing, went on the market in the U.S. with oral capsule through FDA approval in 2003, be used for the prevention of postoperative nausea and vomiting, also the nausea and vomiting that can prevent chemotherapeutic to cause with other antiemetic coupling.Disclose first among the WO9516679 compound A Rui smooth, chemistry 5-[[(2R by name, 3S)-2-[(1R)-1-[3, two (trifluoromethyl) phenyl of 5-] oxyethyl group]-3-(4-fluorophenyl)-4-morpholinyl] methyl]-1,2-dihydro-3H-1,2,4-triazole-3-ketone group, structure is suc as formula shown in the I.
(2R, 3R)-2-[(1R)-1-[3, two (trifluoromethyl) phenyl of 5-] oxyethyl group]-3-(4-fluorophenyl) morpholine is for preparing A Rui smooth key intermediate, and its structure is suc as formula shown in the II.
At present, disclosed both at home and abroad this intermediates preparation is as follows:
(1) disclose among the WO0196319A1 a kind of (2R, 3R)-2-[(1R)-1-[3, two (trifluoromethyl) phenyl of 5-] oxyethyl group]-preparation method of 3-(4-fluorophenyl) morpholine.Concrete steps are with (2S; 3R)-and 3-(4-fluorophenyl)-4-(R)-1-styroyl) morpholine-2-alcohol 1 is starting raw material; obtain hydroxyl activated intermediate 2 with the chloromethyl cyanide reaction; under the effect of boron trifluoride diethyl etherate, obtain intermediate 4, obtain the target product II by Pd/C hydrogenation deprotection again with 3 condensations.In this route, the first step reaction intermediate 2 poor stabilities, quality product is difficult to control in the amplification process.In addition, raw material 3 is that reduction prepares through chiral catalyst, costs an arm and a leg.Therefore this route is difficult to satisfy industrial production requirement.
(2) disclose among the WO2007044829A2 and a kind ofly set out by raceme 4-benzyl-3-(4-fluorophenyl) morpholine-2-alcohol 5; with 1-(1-bromotrifluoromethane)-3; two (trifluoromethyl) phenyl reactions of 5-; prepare intermediate 7; get intermediate 8 through Pd/C hydrogenation deprotection again; with the acetonitrile purifying of pulling an oar, split by L (-)-camphor-10-sulfonic acid again and obtain the target product II.Each intermediate good stability of this route avoids having used expensive intermediate 3.But route later stage intermediate 8 comprises 4 kinds of possibility isomer, this route obtains target isomer by means purifying such as making beating and fractionations, and purification procedures is loaded down with trivial details, and resolution yield is low, the whole piece route exists that loss of material is serious, isomer is difficult for reclaiming problems such as Atom economy difference.
(2R, 3R)-2-[(1R/S)-1-[3, two (trifluoromethyl) phenyl of 5-] oxyethyl group]-3-(4-fluorophenyl) alkylbenzyldimethylasaltsum saltsum 13, can split compound or its salt shown in the acquisition formula II by methods such as recrystallizations.
Prepare (2R at present, 3R)-2-[(1R/S)-1-[3, two (trifluoromethyl) phenyl of 5-] oxyethyl group]-method of 3-(4-fluorophenyl) alkylbenzyldimethylasaltsum saltsum, method as the WO0196319A1 bibliographical information, but, there is the defective of severe reaction conditions, complex process and reagent costliness in this method, can not satisfy need of industrial production.
Summary of the invention
That the object of the invention is to provide is a kind of (2R, 3R)-2-[(1R/S)-1-[3, two (trifluoromethyl) phenyl of 5-] oxyethyl group]-preparation method of 3-(4-fluorophenyl) morpholine or its salt, to overcome the above-mentioned defective that prior art exists.
Method of the present invention comprises the steps:
(1), obtains the compound of formula (12) with the compound condensation shown in morpholine-2-alcohol derivate shown in the formula (1) and the formula (11);
(2) compound shown in the formula (12) is removed protecting group base on the nitrogen-atoms, from reaction system, collect then and obtain (the 2R shown in the formula (13), 3R)-2-[(1R/S)-and 1-[3, two (trifluoromethyl) phenyl of 5-] oxyethyl group]-3-(4-fluorophenyl) morpholine or its salt;
Reaction expression is as follows:
Wherein: X is a leavings group, preferably Cl, Br, I, mesyloxy or tolysulfonyl oxygen base;
Y is acid, preferably hydrochloric acid, sulfuric acid, acetic acid, oxalic acid, methylsulfonic acid, tosic acid or tartrate
R is phenyl, 4-aminomethyl phenyl, 4-methoxy-benzyl or 4-F-phenyl;
Preferably, morpholine-2-alcohol derivate shown in the formula (1) and formula (11) compound condensation obtain the method for the compound of formula (12), comprise the steps:
Compound shown in the formula (1) in solvent, in the presence of alkaline matter, with the reaction of formula (11) compound, is collected the compound that obtains formula (12) then from reaction product;
The compound of formula (1) is commercially available, also can be with reference to WO02088088, Journal of Organic Chemistry, and 2002,67,6743-6747 and Tetrahedron Letter, 48(2007) the 8001-8004 method is synthetic obtains;
Formula (11) compound can be with reference to Tetrahedron Letter, and 48(2007) the 8001-8004 method is synthetic obtains;
Described solvent does not have special requirement, can be selected from water, acetone, ethyl acetate, DMF(N, dinethylformamide), the DMSO(dimethyl sulfoxide (DMSO)), the NMP(N-methyl-2-pyrrolidone), in tetrahydrofuran (THF), dioxane, toluene or the acetonitrile more than one; Preferred solvent is more than one in DMF, DMSO, NMP, dioxane or the toluene, and preferred solvent is DMF, dioxane or toluene;
Described alkaline matter is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium ethylate, sodium methylate, potassium tert.-butoxide, sodium hydride, yellow soda ash, salt of wormwood or cesium carbonate; Preferably sodium hydroxide, potassium hydroxide, salt of wormwood or cesium carbonate; Preferred alkali is sodium hydroxide or salt of wormwood; The mol ratio of the compound shown in the formula (1), alkaline matter formula (11) compound is:
Compound shown in the formula (1): alkaline matter: formula (11) compound=1: 1～5: 1～5;
When reaction adopts two-phase solvent to carry out, can add phase-transfer catalyst.
Described two-phase solvent refers to the mixture of water and organic phase, and wherein organic phase is organic solvent commonly used, can be selected from ethyl acetate, isopropyl acetate, methylene dichloride, the toluene more than one; Preferably solvent is ethyl acetate, toluene or methylene dichloride; Preferred solvent is methylene dichloride and toluene.
Described phase-transfer catalyst does not have special requirement, can be selected from benzyltriethylammoinium chloride (TEBA), Tetrabutyl amonium bromide, tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate (TBAB), tri-n-octyl methyl ammonium chloride, Dodecyl trimethyl ammonium chloride, the tetradecyl trimethyl ammonium chloride more than one; Preferably more than one in benzyltriethylammoinium chloride (TEBA), Tetrabutyl amonium bromide, tetrabutylammonium chloride, the 4-butyl ammonium hydrogen sulfate (TBAB) are more preferably Tetrabutyl amonium bromide or 4-butyl ammonium hydrogen sulfate (TBAB).
The amount of phase-transfer catalyst is a benchmark with substrate morpholine-2-alcohol derivate quality, is 1%-20%, is preferably 10%-15%.
Preferred temperature of reaction is 30～100 ℃, and preferred temperature is 40～60 ℃; The preferred reaction times is 1～15 hour, and the preferred reaction times is 3～8 hours;
Preferably, the compound of formula (12) removes protecting group on the nitrogen-atoms, collects the method for the compound or its salt that obtains formula (13), comprises the steps:
Formula (12) compound in solvent, in the presence of catalyzer, is carried out the catalytic hydrogenation deprotection;
Described solvent is selected from primary alconol, secondary alcohol, the tertiary alcohol of C1-C4, and preferred solvent is the mixture of methyl alcohol, ethanol, Virahol, propyl alcohol, propyl carbinol, water or alcohol and water.Be more preferably the mixture of methyl alcohol, ethanol or itself and water;
When adopting the mixture of alcohol and water, volumetric concentration is 1～20%.
Selected catalyzer comprises but the metal catalyst that is not restricted to mention, is selected from palladium class catalyzer, as Pd/C, Pd/BaSO4, Pd/CaCO3; Raney Ni, platinum oxide or Lewis acid as boron trifluoride, are preferably Pd/C, more preferably the 5%-10%(quality) Pd/C.
Preferred temperature is 10-70 ℃, and what choosing was more arranged is 30-60 ℃;
The preferred time is 1-50 hour, and the more excellent time is 3-6 hour.
Shortening pressure is optimized for 15-600psi, more is optimized for 30-150psi.
This goes on foot catalytic hydrogenation, also can obtain the salt of formula (13) compound under the catalysis of acid, and acid is not particularly limited, and can be Phenylsulfonic acid, tosic acid, citric acid, hydrochloric acid, oxalic acid, tartrate or sulfuric acid;
Beneficial effect of the present invention is:
Adopt path of preparing compound 13 of the present invention, easy and simple to handle, mild condition, convenient post-treatment, operational path is stable, reagent cheaply is easy to get, and is easy to mass preparation.Compound 13 can be used for preparing A Rui smooth, method than bibliographical information, expensive chiral catalyst, resolution reagent and the reaction conditions of harshness and loaded down with trivial details operating procedure have been avoided using, be more suitable in A Rui smooth suitability for industrialized production positive progressive effect and actual application value that tool is bigger.
The present invention will be further described for following embodiment, provides implementation detail of the present invention, but be not intended to limit protection scope of the present invention.
The specific embodiment mode
Embodiment 1
(2R, 3R)-2[(1R/S)-1-[3, two (trifluoromethyl) phenyl of 5-] oxyethyl group]-3-(4-fluorophenyl) morpholine hydrochloride
With (2S, 3R)-3-(4-fluorophenyl)-4-((R)-1-styroyl) morpholine-2-pure 13.8g, acetone 83g joins in the reactor, 0 ℃ adds 6.4gKOH down, behind the stirring 30min, adds 1-(1-bromotrifluoromethane)-3, two (trifluoromethyl) phenyl 21.2g of 5-, reaction is heated to 40 ℃ of reactions 2 hours, with the reaction solution evaporate to dryness, adds 175ml water and 175ml toluene and stirs 15min, separatory, discard water layer, organic layer is with 175ml washing twice, with its evaporate to dryness, add the dilution of 116ml methyl alcohol, solution is transferred in the autoclave, adds 1.61g10%Pd/C, pressurization 0.5MPa carries out hydrogenation, 50 ℃ were reacted 5 hours down, filter, with the solution evaporate to dryness, the compound 13.1g of acquisition formula (13), yield is 65.5%, HPLC purity: 96.2%.
Detected result is as follows: ESI-MS (m/z): 438[M+1]
+
Embodiment 2
(2R, 3R)-2[(1R/S)-1-[3, two (trifluoromethyl) phenyl of 5-] oxyethyl group]-3-(4-fluorophenyl) morpholine hydrochloride
With (2S, 3R)-3-(4-fluorophenyl)-4-((R)-1-styroyl) morpholine-2-pure 20.2g, DMF101mL joins in the reactor, add as 13.6g potassium tert.-butoxide under 0 ℃, behind the stirring 30min, add 1-(1-bromotrifluoromethane)-3, two (trifluoromethyl) phenyl 30.7g of 5-, reaction was heated to room temperature reaction 10 hours, with the reaction solution evaporate to dryness, added 255ml water and 255ml toluene and stirred 15min, separatory, discard water layer, organic layer is with 255ml washing twice, with its evaporate to dryness, add the 169ml isopropanol, solution is transferred in the autoclave, adds 2.35g10%Pd/C, pressurization 0.5MPa carries out hydrogenation, 50 ℃ were reacted 5 hours down, filter, with the reaction solution evaporate to dryness, the compound 25.0g of acquisition formula (13), yield is 85.5%, HPLC purity: 98.4%
Detected result is as follows: ESI-MS (m/z): 438[M+1]
+
Embodiment 3
(2R, 3R)-2[(1R)-1-[3, two (trifluoromethyl) phenyl of 5-] oxyethyl group]-3-(4-fluorophenyl) morpholine hydrochloride
With (2S, 3R)-3-(4-fluorophenyl)-4-((R)-1-styroyl) morpholine-2-pure 15g, Tetrabutyl amonium bromide 2.25g, toluene 90mL joins in the reactor, drip 10%NaOH solution 70ml under the room temperature, drip 1-(1-methylsulfonyl oxygen ethyl)-3 again, two (trifluoromethyl) phenyl 26.5g of 5-, reaction is heated to 50 ℃ of reactions 6 hours, the reaction solution layering, and separatory gets organic layer, washing (72ml) one time, the organic layer evaporate to dryness adds the dilution of 126ml methyl alcohol, and solution is transferred in the autoclave, add 1.75g10%Pd/C, pressurization 0.5MPa carries out hydrogenation, and 50 ℃ were reacted 5 hours down, filter, with the reaction solution evaporate to dryness, the compound 18.1g of acquisition formula (13), yield 83.4%, HPLC purity: 98.1%
Detected result is as follows: ESI-MS (m/z): 438[M+1]
+
Embodiment 4
(2R, 3R)-2[(1R)-1-[3, two (trifluoromethyl) phenyl of 5-] oxyethyl group]-3-(4-fluorophenyl) morpholine hydrochloride
With (2S, 3R)-3-(4-fluorophenyl)-4-((R)-1-styroyl) morpholine-2-pure 15g, 4-butyl ammonium hydrogen sulfate 2.25g, toluene 90mL joins in the reactor, drip 10%KOH solution 70ml under the room temperature, drip 1-(1-bromotrifluoromethane)-3 again, two (trifluoromethyl) phenyl 19.2g of 5-, reaction is heated to 50 ℃ of reactions 6 hours, reaction solution layering, separatory gets organic layer, washing (72ml) one time, the organic layer evaporate to dryness adds the dilution of 126ml methyl alcohol, solution is transferred in the autoclave, add 1.76g10%Pd/C, 0.57g is to benzene methanesulfonic acid, and pressurization 0.5Mpa carries out hydrogenation, 50 ℃ were reacted 5 hours down, filter, with the reaction solution evaporate to dryness, the compound of acquisition formula (13) to benzene methanesulfonic acid salt 24.4g, yield 80.4%, HPLC purity: 98.6%
Detected result is as follows: ESI-MS (m/z): 438[M+1]
+
Embodiment 5
(2R, 3R)-2[(1R)-1-[3, two (trifluoromethyl) phenyl of 5-] oxyethyl group]-3-(4-fluorophenyl) morpholine hydrochloride
With (2S, 3R)-3-(4-fluorophenyl)-4-((R)-1-styroyl) morpholine-2-pure 18g, 4-butyl ammonium hydrogen sulfate 2.7g, toluene 108mL joins in the reactor, drip weight concentration 10%NaOH solution 84ml under the room temperature, drip 1-(1-bromotrifluoromethane)-3 again, two (trifluoromethyl) phenyl 23g of 5-, reaction is heated to 50 ℃ of reactions 6 hours, the reaction solution layering, and separatory gets organic layer, washing (86ml) one time, the organic layer evaporate to dryness adds the dilution of 151ml methyl alcohol, and solution is transferred in the autoclave, add 2.1g10%Pd/C, 2.18g hydrochloric acid, pressurization 0.5MPa carries out hydrogenation, and 40 ℃ were reacted 5 hours down, filter, the reaction solution evaporate to dryness is obtained the hydrochloride 24.5g of the compound of formula (13), yield 86.7%, HPLC purity: 97.8%
Detected result is as follows: ESI-MS (m/z): 438[M+1]
+
Embodiment 6
The product that obtains with embodiment 1 is a starting raw material, prepares the method for compound salt shown in the formula II:
13.3 formulas (13) compound is mixed with the 14g isopropyl acetate, drip the hydrochloric acid isopropyl acetate solution 31g of 2.5mol/L again, obtain mixing solutions, be heated to 30 ℃ then, stirred 6 hours, be cooled to room temperature, stir the 5h after-filtration, collect the hydrochloride 7.85g of formula II compound, yield 54.5%, HPLC purity: 99.5%de
Detected result is as follows:
[α]D
22=60.3°(C0.97，MeOH)ESI-MS(m/z):438[M+1]
+。；
1H?NMR(400MHz,DMSO-d6)δ11-10(br,2H),7.88(s,1H),7.63(dd,J=8.8,5.3Hz,2H),7.43(s,2H),7.13(t,J=8.8Hz,2H),5.15(q,J=6.5Hz,1H),4.86(d,J=8.3Hz,1H),4.25(d,J=8.3Hz,1H),4.24-4.11(m,2H),3.23-3.15(m,2H),1.33(d,J=6.5Hz,3H)；
Embodiment 7
The product that obtains with embodiment 5 is a starting raw material, prepares the method for compound salt shown in the formula II:
The tosilate of the compound of 24.5g formula (13) is mixed with the 74g Virahol, obtain mixed solution, be heated to 40 ℃, stir 5h, be cooled to room temperature, stir the 5h after-filtration, collect the tosilate 12.5g of formula II compound, yield 51%, HPLC purity: 99.6%de
Detected result is as follows:
[α]D
22=61.0°(C0.97，MeOH)ESI-MS(m/z):438[M+1]
+。；
1H?NMR(400MHz,DMSO-d6)δ11-10(br,2H),7.88(s,1H),7.63(dd,J=8.8,5.3Hz,2H),7.43(s,2H),7.13(t,J=8.8Hz,2H),5.15(q,J=6.5Hz,1H),4.86(d,J=8.3Hz,1H),4.25(d,J=8.3Hz,1H),4.24-4.11(m,2H),3.23-3.15(m,2H),1.33(d,J=6.5Hz,3H)。
Claims (11)
1. (2R, 3R)-2-[(1R/S)-1-[3, two (trifluoromethyl) phenyl of 5-] oxyethyl group]-method for making of 3-(4-fluorophenyl) morpholine or its salt, it is characterized in that, comprise the steps:
(1), obtains the compound of formula (12) with the compound condensation shown in morpholine-2-alcohol derivate shown in the formula (1) and the formula (11);
(2) compound shown in the formula (12) is removed protecting group on the nitrogen-atoms, from reaction system, collect then and obtain (the 2R shown in the formula (13), 3R)-2-[(1R/S)-and 1-[3, two (trifluoromethyl) phenyl of 5-] oxyethyl group]-3-(4-fluorophenyl) morpholine or its salt;
Reaction expression is as follows:
Wherein: X is a leavings group, preferably Cl, Br, I, mesyloxy or tolysulfonyl oxygen base;
Y is acid;
R is phenyl, 4-aminomethyl phenyl, 4-methoxy-benzyl or 4-F-phenyl.
2. method according to claim 1 is characterized in that, Y is hydrochloric acid, sulfuric acid, acetic acid, oxalic acid, methylsulfonic acid, tosic acid or tartrate.
3. method according to claim 1 is characterized in that, morpholine-2-alcohol derivate shown in the formula (1) and formula (11) compound condensation obtain the method for the compound of formula (12), comprise the steps:
Compound shown in the formula (1) in solvent, in the presence of alkaline matter, with the reaction of formula (11) compound, is collected the compound that obtains formula (12) then from reaction product.
4. method according to claim 3 is characterized in that, temperature of reaction is 30～100 ℃; Reaction times is 1～15 hour.
5. method according to claim 3 is characterized in that, the mol ratio of the compound shown in the formula (1), alkaline matter formula (11) compound is: the compound shown in the formula (1): alkaline matter: formula (11) compound=1: 1～5: 1～5.
6. method according to claim 3, it is characterized in that, described solvent is selected from water, acetone, ethyl acetate, DMF(N, dinethylformamide), the DMSO(dimethyl sulfoxide (DMSO)), the NMP(N-methyl-2-pyrrolidone), in tetrahydrofuran (THF), dioxane, toluene or the acetonitrile more than one;
Described alkaline matter is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium ethylate, sodium methylate, potassium tert.-butoxide, sodium hydride, yellow soda ash, salt of wormwood or cesium carbonate.
7. according to each described method of claim 2～6, it is characterized in that, when reaction adopts two-phase solvent to react, add phase-transfer catalyst;
Described two-phase solvent refers to the mixture of water and organic phase, and wherein organic phase is an organic solvent;
Described phase-transfer catalyst is selected from benzyltriethylammoinium chloride (TEBA), Tetrabutyl amonium bromide, tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate (TBAB), tri-n-octyl methyl ammonium chloride, Dodecyl trimethyl ammonium chloride, the tetradecyl trimethyl ammonium chloride more than one; More than one in benzyltriethylammoinium chloride (TEBA), Tetrabutyl amonium bromide, tetrabutylammonium chloride, the 4-butyl ammonium hydrogen sulfate (TBAB) preferably;
The amount of phase-transfer catalyst is a benchmark with substrate morpholine-2-alcohol derivate quality, is 1%-20%.
8. method according to claim 1 is characterized in that, the compound of formula (12) removes protecting group on the nitrogen-atoms, collects the method for the compound or its salt that obtains formula (13), comprises the steps:
Formula (12) compound in solvent, in the presence of catalyzer, is carried out the catalytic hydrogenation deprotection;
Selected catalyzer comprises but is not restricted to palladium class catalyzer or Lewis acid.
9. method according to claim 7 is characterized in that, temperature of reaction is 10-70 ℃, and the reaction times is 1-50 hour, and shortening pressure is 15-600psi.
10. method according to claim 1; it is characterized in that the compound of formula (12) removes protecting group on the nitrogen-atoms, collect the method for the compound or its salt that obtains formula (13); comprise the steps: under the catalysis of acid, to carry out, obtain the salt of formula (13) compound.
11., it is characterized in that described solvent is selected from the mixture of the primary alconol, secondary alcohol, the tertiary alcohol of C1-C4 or itself and water according to claim 7,8 or 9 described methods.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104496930A (en) * | 2014-12-30 | 2015-04-08 | 江苏阿尔法药业有限公司 | Preparation method of optical-purity aprepitant raw medicine intermediate |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104496930A (en) * | 2014-12-30 | 2015-04-08 | 江苏阿尔法药业有限公司 | Preparation method of optical-purity aprepitant raw medicine intermediate |
| CN104496930B (en) * | 2014-12-30 | 2016-05-25 | 江苏阿尔法药业有限公司 | A kind of optical purity Aprepitant bulk drug intermediate preparation method |
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